This proposal represents an application for a Research Career Award (K02) focused on the candidate's long-term goal of developing agents, which attenuate the toxic effects of drugs of abuse. The approach to achieving this goal is to have a research program that seeks to solve problems associated with drug abuse and dependence through testing hypotheses with chemistry-based approaches. The proposed research plan comprises of three projects, sharing the common theme of developing agents to attenuate the potentially lethal effects of drugs of abuse. In the case of opioids, the goal is to develop morphine-like analgesics which do not give rise to the severe constipation seen with current agents; for cocaine, the goal is to develop sigma receptor-based agents as potential treatments for cocaine overdose; for GHB, the goal is to develop a treatment for GHB overdose based on a mixed profile of GHB and GABA-B antagonism. My short-term approach to the latter two goals is to develop the current collaborations with Drs. France and Matsumoto to a point where I am able to take the lead as PI on new R01 submissions. My plans for the opioids is to develop a new research program based on pharmacokinetic mechanisms of tolerance, and initially submit an R21 application to gain valuable preliminary data. This approach is based on the hypothesis that as tolerance is reduced, the ever-increasing doses of morphine (which leads to the constipation) will not be required. My long-tern career goal is to develop these projects and my collaborations to the point where I am able to translate these medications into the clinic or emergency room. The candidate will spend 75% of his time on NIH-funded research. This award will allow the candidate to be relieved from many teaching and administrative responsibilities, thereby allowing him to focus on current and future research projects.